Long-Term Follow-up of KEYNOTE-590: Benefit of Pembrolizumab Plus Chemotherapy Affirmed in Advanced Esophageal Cancer

Long-term follow-up of the phase III KEYNOTE-590 trial has confirmed the benefit of pembrolizumab plus chemotherapy in advanced esophageal cancer. As compared with chemotherapy alone, after a median follow-up of almost 59 months, patients treated with the chemoimmunotherapy combination were three times more likely to be alive at 5 years, with no appreciable increase in adverse events, according to Manish A. Shah, MD, of Weill Cornell Medical College, New York, who reported these findings at the 2024 ASCO Gastrointestinal Cancers Symposium (Abstract 250).

Manish A. Shah, MD

“There was a persistent and sustained difference in overall survival in the intention-to-treat population extending past 5 years,” said Dr. Shah, who reported the 5-year overall survival rate was 10.6% with pembrolizumab plus chemotherapy vs 3.0% with chemotherapy alone. “Achieving a 10% long-term survival rate is remarkable…. These data continue to support the use of pembrolizumab plus chemotherapy for advanced esophageal cancer as first-line therapy.”

About KEYNOTE-590

As previously reported by Sun et al in The Lancet, KEYNOTE-590 enrolled 749 patients with locally advanced or metastatic esophageal adenocarcinoma, esophageal squamous cell carcinoma, or gastroesophageal junction adenocarcinoma. Patients were randomly assigned to receive chemotherapy (5-FU and cisplatin), plus up to 35 cycles of pembrolizumab or placebo. The primary endpoints of the trial were overall survival and progression-free survival in the intention-to-treat population.

At the first interim analysis, after a median follow-up of 22.6 months, pembrolizumab plus chemotherapy significantly improved overall survival (hazard ratio [HR] = 0.73) and progression-free survival (HR = 0.65), establishing this approach as a first-line standard of care.

Updated Results

In the updated analysis, pembrolizumab plus chemotherapy led to a significant improvement in overall survival, with a median overall survival of 12.3 months vs 9.8 months with chemotherapy alone (HR = 0.72). Significant benefits were also seen in the patient subsets with esophageal squamous cell carcinoma (n = 548), those with a combined positive score (CPS) of ≥ 10 (n = 383), and those with esophageal squamous cell carcinoma and a CPS ≥ 10 (n = 286; Table 1).

Table 1: Overall Survival at 5 Years in KEYNOTE-590

Median progression-free survival was 6.3 months with pembrolizumab/chemotherapy vs 5.8 months with chemotherapy (HR = 0.64). Hazard ratios were 0.65 for the esophageal squamous cell carcinoma subset, 0.51 for the CPS ≥ 10 subset, and 0.53 for patients with esophageal squamous cell carcinoma and a CPS ≥ 10. No patient in the control arm was alive without disease progression after 3 years, whereas 8% of those in the experimental arm remained progression-free at that time. Quality-of-life outcomes were similar in the intention-to-treat population and prespecified subgroups.

Dr. Shah noted the 3% of patients still alive at 5 years after treatment with chemotherapy alone all had localized unresectable disease and had a “great response to chemotherapy.”  As for the 10% of patients alive at 5 years in the chemoimmunotherapy arm, one-third had liver metastases, “and we were still able to eradicate that with this treatment,” he said.

“We need to dive more into what happened to patients if they were rendered no evidence of disease,” added Dr. Shah. The ongoing RENAISSANCE study is addressing the issue of whether eradication of limited metastatic disease improves outcomes, he said.

Disclosure: Dr. Shah reported financial relationships with Astellas Pharma, Bristol Myers Squibb, and Oncolys BioPharma.